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Evidence that the dephosphorylation of Ser(535) in the epsilon-subunit of eukaryotic initiation factor (eIF) 2B is insufficient for the activation of eIF2B by insulin

Record type: Article

Eukaryotic initiation factor (eIF) 2B is a guanine-nucleotide exchange factor that plays a key role in the regulation of protein synthesis. It is activated by insulin, serum and other agents that stimulate general protein synthesis. The largest (e) subunit of eIF2B is a substrate for glycogen synthase kinase (GSK)-3 in vitro, and phosphorylation by GSK3 inhibits the activity of eIF2B. The site of phosphorylation has previously been identified as Ser535. GSK3 is inactivated by phosphorylation in response to insulin or serum. In Chinese-hamster ovary cells, insulin and serum bring about the dephosphorylation of Ser535 in vivo, concomitantly with the phosphorylation of GSK3, and these effects are mediated through signalling via phosphoinositide 3-kinase. We have made use of inhibitors of GSK3 to determine whether GSK3 is responsible for phosphorylation of Ser535 in vivo and to explore the role of phosphorylation of Ser535 in the regulation of eIF2B. Treatment of cells with LiCl or with either of two recently developed GSK3 inhibitors, SB-415286 and SB-216763, brought about the dephosphorylation of Ser535, which strongly indicates that this site is indeed a target for GSK3 in vivo. However, these compounds did not elicit significant activation of eIF2B, indicating, consistent with conclusions from one of our previous studies, that additional inputs are required for the activation of eIF2B. Our results also show that each of the inhibitors used affects overall protein synthesis and have additional effects on translation factors or signalling pathways apparently unrelated to their effects on GSK3, indicating that caution must be exercised when interpreting data obtained using these compounds.

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Citation

Wang, X.M., Janmaat, M., Beugnet, A., Paulin, F.E.M. and Proud, C.G. (2002) Evidence that the dephosphorylation of Ser(535) in the epsilon-subunit of eukaryotic initiation factor (eIF) 2B is insufficient for the activation of eIF2B by insulin Biochemical Journal, 367, (2), pp. 475-481.

More information

Published date: 1 October 2002
Keywords: glycogen synthase kinase 3, mRNA translation, mammalian target of rapamycin (mTOR)

Identifiers

Local EPrints ID: 56139
URI: http://eprints.soton.ac.uk/id/eprint/56139
ISSN: 1470-8728
PURE UUID: c046f4bc-443b-4351-844f-9600e69c8001

Catalogue record

Date deposited: 06 Aug 2008
Last modified: 17 Jul 2017 14:31

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Contributors

Author: X.M. Wang
Author: M. Janmaat
Author: A. Beugnet
Author: F.E.M. Paulin
Author: C.G. Proud

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